With the long-term objective of discovering new relationships between the metabolism and biologic activity of medically-important esters, the proposed research aims to identify factors that increase or decrease the detoxifying actions of malathion carboxylesterase, meperidine carboxylesterase, and other carboxylesterase of toxicologic interest. The proposed studies will produce data on how the esterases of interest will be affected when the animal is exposed to selected drugs, food additives, pesticides and other xenobiotics, and how the enzyme activities may change during the lifespan of the animal. Then, having ways and means to alter carboxylesterase titers, the significance of altered esterase levels will be explored with bioassays of ester potency--dose-response studies will be done in animals having low, normal and high esterase levels and, in the case of meperidine, in animals having altered esterase/oxidase ratios. Structure-activity studies will be done to compare the substrate specificities of ethylesterases on rat liver, lung, kidney, brain, testis and serum. The data from these studies and from companion electrophoresis studies will serve to compare and contrast the ethylesterases distributed among rat organs. Based on the results of these studies, ethylesterase assays to diagnose organ damage will be designed and tested. The results of the integrated biochemical and toxicological studies should improve understanding of the processes by which individuals could either become sensitized or desensitized to the effects of medically-important esters. With an understanding of how carboxylesterases can be regulated, and how changes in activity effect the ester's toxicity, it may be possible to prescribe carboxylesterase boosters or attenuators to improve the efficacy or diminish the toxicity of the prescribed ester. It should also be possible to predict adverse interactions before they occur, and recognize them as factors that might be compromising therapy. The results of the ethylesterase distribution/structure activity studies should be of practical value in drug design (i.e. synthesis of tissue-specific ethylesters) and should lead to the development of new inexpensive and effective assays for the assessment of organ damage.